Sanofi T2D Combo Injection Wins FDA Panel Support

Close to unanimous approval of the insulin glargine/lixisenatide combination

SILVER SPRING -- An FDA advisory committee threw its support behind a new combination diabetes drug, despite major concerns about the product's unique design and labeling.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 12 to 2, with one abstention, to recommend approval of Sanofi's insulin glargine and lixisenatide injection also known as IGlarLixi -- a fixed ratio product proposed for treating adults with type 2 diabetes.

To date, all approved antidiabetic combinations are either made of two individual fixed dose products or two individual titratable products. This new dual therapy combines a fixed dose product -- the GLP-1 agonist -- and a titratable product -- insulin.

"I feel that this combination delivered in this manner meets clinical need with adequate efficacy," said Robert Smith, MD, committee chair and a professor at Brown University.

Smith noted that his recommendation was contingent upon adequately addressing concerns around the device delivery, and the need to develop appropriate procedural guidance, as well as a need for postmarketing studies to monitor serious allergic reactions.

Steven Meisel, PharmD, of Fairveiw Health Services in Minneapolis, voted against approval, highlighting issues with the labeling of the delivery device.

"We have to come up with some dose combination that is not strictly 10 units or 20 units," he said noting that the device references only the insulin dose and not the amount of lixisenatide. "It sets up the mental model that all this is is just insulin."

Most panel members who voted to support a recommendation voiced reservations similar to Meisel's related to the either the current labeling of the proposed injectable pens or its design or both, but those reservations didn't deter them from a positive recommendation. Smith also suggested redesigning the pens to prevent any misunderstandings.

While there were lingering concerns around allergic risks and the possibility of elevated antibodies, the committee did not find any safety or efficacy signals for lixisenatide alone to preclude approval of the combination drug. Smith said he found the cardiovascular data "reassuring."

The committee also explored concerns around the fixed dosage, the capping of one drug component that is generally titratable -- insulin -- and the potential for an allergic reaction.

FDA technical staff did find a signal for anaphylaxis and hypersensitivity, "the magnitude of the risk in the post marketing setting is unknown," it said. But the consensus of the panel seemed to be that postmarket monitoring was adequate for studying this signal.

Jean-Marc Guettier, MD, director of the FDA's Division of Metabolism and Endocrinology, pointed out the concerns around the inability to adjust or titrate the dosing of one drug without adjusting the other as a concern, and stressed the "efficacy and safety of concurrent use may be affected by this limitation."

Asked to define a target population for the product, specifically whether patients who are insulin naive should be started on a combination therapy or whether the treatment should be used as an add-on therapy after one component of the combination has been tried. The committee was more inclined to support the combination product as an add-on therapy.

In briefing documents posted on Monday, the agency shared its reservations over the superiority of the combination drug, particularly since lixisenatide alone has not been shown to offer benefit at the low dosage it would be given as part of iGlarLixi.

The sponsors argued in their presentation that the benefit of their combination product was that it increased glycemic control, did not require counting carbs, and simplified delivery by requiring fewer injections.

The agency emphasized that in developing fixed combination drug products, each component must pull its weight. In other words, "Two or more drugs may be combined in a single dosage form when each agent component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy," as Guettier explained.

In the case of diabetic combination drugs, the all-important "claimed effect" is "improving glycemic control," which is generally measured by a 6-month change in hemoglobin A1c (HbA1c) concentration from baseline.

In two phase 3 studies, the FDA technical staff found that iGlarLixi "demonstrated superiority to insulin glargine and lixisenatide" from baseline to 30 weeks." The staff however did point out that the "contribution of low doses of lixisenatide to the effect of iGlarLixi on HbA1c change is uncertain." In transitioning from one single drug to a combination some patients would be required to lower the dose of lixisenatide they received.

As Guettier noted, "The clinical logic of going down on the dose of a presumably active drug in a patient requiring additional glucose control is not apparent to us."

Though the FDA is not required to follow the recommendations of its advisory committees, it usually does.

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